Bcl-2-independent Bcr–Abl-mediated resistance to apoptosis: protection is correlated with up regulation of Bcl-xL (original) (raw)

Oncogene volume 16, pages 1383–1390 (1998)Cite this article

Abstract

Bcr–Abl is the molecule responsible for both the transformation phenotype and the resistance to chemotherapeutic drugs found in chronic myelogenous leukemia (CML) cells. Wild-type HL-60, a transformed pro-myelocytic cell line, is very susceptible to apoptosis-inducing agents. We show here that expression of Bcr–Abl in HL-60 cells rendered them extremely resistant to apoptosis induced by a wide variety of agents. The anti-apoptotic effect of Bcr–Abl was found to be independent of the phase of the cell cycle. Treatment with antisense oligonucleotides directed to bcr decreased the expression of the ectopic bcr–abl and restored susceptibility to apoptosis. Double mutations affecting the autophosphorylation site and the phosphotyrosine-binding motif (FLV**R**ES) have been previously shown to impair the transforming activity of Bcr–Abl in fibroblasts and hematopoietic cells, however HL-60 cells expressing this double mutant molecule exhibited the same level of resistance to apoptosis as those expressing the wild-type Bcr–Abl. Interestingly, wild type and mutant Bcr–Abl induced in HL-60 cells a dramatic down regulation of Bcl-2 and increased the levels of Bcl-xL. The level of Bax did not change in response to the presence of Bcr–Abl. Antisense oligonucleotides targeted to bcl-x down-regulated the expression of Bcl-xL and increased the susceptibility of HL-60.Bcr–Abl cells to staurosporine. Importantly, HL-60 cells overexpressing Bcl-xL showed higher expression of Bcl-xL but lower resistance to apoptosis when compared to HL-60.Bcr–Abl cells. The results described here show that Bcr–Abl is a powerful mammalian anti-apoptotic molecule and can act independently of Bcl-2. Bcl-xL, however, seems to participate in part in Bcr–Abl-mediated resistance to apoptosis in HL-60 cells.

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  1. Gustavo P Amarante-Mendes
    Present address: Departmento de Imunologia, Instituto de Ciências Biomédicas, Universidade de Sáo Paulo, Sáo Paulo, 05508-900, Brazil

Authors and Affiliations

  1. Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego
    Gustavo P Amarante-Mendes, Anne J McGahon, Walter K Nishioka & Douglas R Green
  2. 92121, California, USA
    Gustavo P Amarante-Mendes, Anne J McGahon, Walter K Nishioka & Douglas R Green
  3. Department of Microbiology and Molecular Genetics, Molecular Biology Institute, and Howard Hughes Medical Institute, University of California–Los Angeles, Los Angeles, 90024–1662, California, USA
    Daniel EH Afar & Owen N Witte

Authors

  1. Gustavo P Amarante-Mendes
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  2. Anne J McGahon
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  3. Walter K Nishioka
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  4. Daniel EH Afar
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  5. Owen N Witte
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  6. Douglas R Green
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Amarante-Mendes, G., McGahon, A., Nishioka, W. et al. Bcl-2-independent Bcr–Abl-mediated resistance to apoptosis: protection is correlated with up regulation of Bcl-xL.Oncogene 16, 1383–1390 (1998). https://doi.org/10.1038/sj.onc.1201664

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